Categories of Delayed-type Hypersensitivity Drug Rashes

Common (>80%)
Exanthematous drug eruptions (aka morbilliform or maculopapular drug eruptions)	Appear 4-21 days after starting the drug Patients with HIV or BMT are at increased risk Rash appearance variable Maculopapular or morbiliform eruptions - often characterized by pink-to-red macules and papules (often pruritic) that spread rapidly and may coalesce; scaling/peeling can occur with resolution of the exanthem Usually begins on trunk, spreads to extremities, typically symmetric Urticarial lesions, angioedema, fixed drug eruptions, photosensitivity are less common manifestations of drug eruptions
Less Common
Urticaria and/or angioedema	These symptoms can also be non-IgE-mediated Urticaria is the most common skin manifestation of serum sickness; however, the presence of maculopapular lesions on the sides of the fingers and toes or a serpiginous distribution of such lesions along the lateral aspects of both soles might be more specific
Fixed drug eruptions	Can present as eczematous lesions, papules, vesicles, or urticaria and occasionally involve the oral mucosa Common anatomic locations include the lips, hands, and genitalia (especially males) Often appear round or oval, sharply demarcated, red to livid, slightly elevated plaques ranging from a few mm to cm in diameter Typically occur within 1-2 wks of drug exposure but might recur more rapidly with re-exposure
Erythema multiforme major	Target lesions with or without blisters Compared to SJS, causes symmetric, mainly acral lesions, and mucosal involvement is less severe and less frequently involves 2 or more mucosal lesions Occurs mainly after HSV infection and less frequently is drug induced, and the prognosis is usually benign
Acneiform
Pruritus
Uncommon
Acanthosis nigricans Alopecia Aphthous stomatitis Black hairy tongue Bullous eruptions Erythema nodosum Exfoliative dermatitis Gingival hyperplasia Lichenoid eruptions Lupus erythematosus Phototoxic/photoallergic Pigmentation Pityriasis rosea–like eruptions Psoriasis Purpura Vasculitis
Severe
AGEP	Rare, begins with erythema or edema in the intertriginous areas or face followed by generalized fine nonfollicular sterile pustules. Fever, neutrophilia, and eosinophilia can also be present. Should be distinguished from other causes of infectious pustules, such as candidiasis, gonococcemia, impetigo, and bacterial folliculitis
SJS/TEN	Large scale epidermal death (mucous membrane erosions, target lesions, and epidermal necrosis with detachment), almost always drug-induced Hallmarks include fever (universal), conjunctivitis, pharyngitis, pruritis, painful skin SJS is usually classified as <10% BSA involvement, TEN >30% BSA, 10-30% is overlap syndrome Multi-organ involvement can occur Mortality 5-10% for SJS, 30-50% for TEN
DRESS

Comparison

Onset of Delayed Drug Rashes (Pichler)

Drug-HLA-Severe Rash Associations

High = point estimate relative risk ≥ 10 and significant and/or incidence ≥1 per 10,000 users
Mid = point estimate of relative risk ≥ 5 and < 10 and significant
SA = Suspected association based on detection of genetic association of increased risk of hypersensitivity reactions to this drug which is highly likely to include cases of DRESS with this drug or ≥ 5 suspect cases
†Whites ‡Han Chinese and/or other non-Japanese Asians §Japanese ¶ pooled estimate for all antiepileptic drugs listed below

Drug-Reaction Associations

Drugs rarely causing cutaneous eruptions

Antacids Antihistamines (oral) Atropine Benzodiazepines Corticosteroids Digoxin Ferrous sulphate Insulin Laxatives Local anaesthetics (other than topical) Muscle relaxants Nitrates Nystatin Oral contraceptives Propranolol Spironolactone Theophylline Thyroid hormones Vitamins

Drugs commonly causing exanthematous reactions

Allopurinol Antimicrobials: cephalosporins, penicillins, chloramphenicol, erythromycin, gentamicin, amphotericin, antituberculous drugs, nalidixic acid, nitrofurantoin, sulfonamides Barbiturates Captopril Carbamazepine Furosemide Gold salts Lithium Phenothiazines Phenylbutazone Phenytoin Thiazides

Drugs commonly causing fixed drug eruption

ACE inhibitors Allopurinol Antimicrobials: co-trimoxazole, sulfonamides, tetracyclines, cephalosporins, penicillin, clindamycin, trimethoprim, metronidazole Barbiturates Benzodiazepines Calcium channel blockers: amlodipine, diltiazem Carbamazepine Dextromethorphan Diltiazem Fluconazole Lamotrigine NSAIDs, including aspirin Paclitaxel Paracetamol Phenolphthalein Proton pump inhibitors: omeprazole, lansoprazole Quinine Salicylates Terbinafine

Drugs commonly causing psoriasiform eruptions or exacerbate psoriasis

ACE inhibitors Beta-blockers Chloroquine and hydroxychloroquine Digoxin Gold Granulocyte colony-stimulating factor (G-CSF) Interferons Lithium NSAIDs Penicillamine Terbinafine Tetracyclines TNF-alpha antagonists

Drugs commonly causing cutaneous vasculitic reactions

Allopurinol Aspirin Beta-lactam antibiotics Carbamazepine Carbimazole Co-trimoxazole Diltiazem Erythromycin Furosemide Gold Haemopoietic growth factors (G-CSF and GM-CSF) Hydralazine Interferons Methotrexate Minocycline NSAIDs Penicillamine Propylthiouracil Retinoids Sulfasalazine Sulfonamides Thiazides Thrombolytic agents

Drugs commonly causing EMM, SJS, TEN

Allopurinol Anti-tuberculous drugs Barbiturates Beta-lactam antibiotics* Carbamazepine* Chlorpropamide Co-trimoxazole Gold Griseofulvin Histamine H2-antagonists Lamotrigine* Leflunomide Macrolides Mefloquine Nevirapine* Nitrofurantoin NSAIDs (expecially oxicams)* Pantoprazole* Phenothiazines Phenytoin* Rifampicin Salicylates Sertraline* Sulfonamides* Tetracyclines Thiazides Tramadol*

*Higher risk for SJS/TEN

Drugs commonly causing blistering drug eruptions
Pemphigus	Captopril Cephalosporins Penicillin Penicillamine Piroxicam Gold/sodium aurothiomalate
Bullous pemphigoid	Furosemide ACE inhibitors (captopril, enalapril) Penicillin Penicillamine Chloroquine Sulfasalazine
IgA bullous dermatosis	Captopril Ceftriaxone Co-trimoxazole Furosemide G-CSF Interleukin-2 Lithium NSAIDs Penicillin Rifampicin Vancomycin
Pseudoprophyria cutanea tarda	NSAIDs Tetracycline Thiazides Furosemide

Drugs commonly causing photosensitivity reactions
Frequent Amiodarone NSAIDs Phenothiazines (particularly chlorpromazine) Retinoids Sulfonamides Tetracyclines (particularly demeclocycline) Thiazides	Less frequent Antidepressants (tricylic, MAOIs) Antifungals Antimalarials Benzodiazepines Beta-blockers Carbamazepine Griseofulvin Oral contraceptives Quinine Quinolones Retinoids St John’s Wort Sulphonylureas

Drugs associated with other integumentary changes

Pigmentation Amiodarone (slate grey) Chloroquine (blue-grey or brown) Chlorpromazine (blue-grey) Cytotoxic agents Gold (blue-grey) Hydroxychloroquine Imatinib Mepacrine (yellow) Minocycline Oral contraceptives (brown) Phenytoin (brown) Alopecia Amphetamines Anticoagulants (warfarin, heparin, heparinoids) Antidepressants Antithyroid drugs Beta-blockers Carbamazepine Cimetidine Cytotoxic agents Hypolipidaemics Interferons Leflunomide Lithium Oral contraceptives Phenytoin Retinoids Tamoxifen Valproate Hypertrichosis Androgens Ciclosporin Diazoxide Methoxsalen Minoxidil Nifedipine Penicillamine Phenytoin Verapamil Nail disorders Captopril Chloramphenicol Chlorpromazine Cytotoxic agents Fluoroquinolones Gold Lithium Methoxsalen Penicillamine Phenytoin Retinoids Tetracyclines Thiazides

Drugs commonly causing eczematous reactions

Gold: lichenoid features, may progress to erythroderma Bleomycin Penicillin Chloramphenicol Quinine Beta-blocker Methyldopa Clonidine

Diagnosis

• H&P alone is often sufficient
• Signs of a serious drug rash that should always be identified:

Lab Testing (Pichler)

• LFTs - in patients with severe/generalized maculopapular rashes, 25% will have liver inflammation
• CBC/diff
  • Eosinophilia (>0.6 g/L) is common (50%) and typical for delayed drug hypersensitivity
  • Presence of activated atypical lymphocytes is a sign of severe delayed drug hypersensitivity reaction (also seen in acute EBV, acute HIV, acute Still's disease)
• BUN/Cr may demonstrate renal involvement
• CRP may be normal or elevated
• Lymphocyte transformation tests are specific but not sensitive

Skin Biopsy

• When diagnosis is less clear, biopsies can aid in differentiating vasculitis, bullous diseases, and contact dermatitis
  • Note that there are no absolute histologic criteria for the diagnosis of drug-induced eruptions, and biopsy might not definitively exclude alternative causes
  • Histopathologic features of interface dermatitis, spongiosis, and tissue eosinophilia are not specific and can be seen with other cutaneous diseases.
• Best lesions to biopsy are evolving or recent skin lesions, and the biopsy should be performed at the edge of the lesion
• Immunofluorescence stains are important in the evaluation of bullous lesions

Drug Challenge

Drug Rash Likelihood Algorithm (Stern)

References